The present invention relates to the reduction of breast density with 4-hydroxy tamoxifen (4-OHT). It also relates to improvements in mammographic sensitivity and to reductions in breast cancer risks that attend a reduction in breast density.
The density of a patient's breast tissue depends on the relative proportions of adipose tissue (fat), connective tissue and epithelial tissue. Adipose tissue is the least dense of these three, while connective tissue and epithelial tissue are relatively dense. Thus, breast density is directly proportional with connective and epithelial tissue content. Overall breast composition can range from tissue composed entirely of fat, to tissue predominated by diffuse and/or nodular densities.
The composition of an individual's breast tissue frequently varies over time. For example, breast density inversely correlates with age, postmenopausal status, number of births, and declining body weight. These correlations suggest that histologic changes associated with breast density are under hormonal control. Indeed, women who have dense breasts, as determined by mammography, have higher serum estrogen concentrations than women with less dense breasts. Moreover, estrogen replacement therapy is associated with increased breast density in postmenopausal women (Leung et al., 1997; Saftlas et al., 1987; Jenks et al., 1994; Kaufman et al., 1993).
Dense breast tissue carries at least two important health implications. First, it is one predictor of breast cancer risk (Wolfe, 1976). In fact, studies have shown that high mammographic breast density indicates a 4- to 6-fold increased risk of breast cancer (Byrne et al., 1997; Boyd et al., 1992, 1995). The association between breast density and breast cancer risk appears to stem from increased stromal and epithelial cell proliferation in dense breast tissues.
A second important implication of dense breast tissue is that it affects mammographic sensitivity (Kerlikowske et al., 1996; Ma et al., 1992). This is critical because of current widespread reliance on mammography for cancer detection. Less dense breast tissue, which is dominated by adipose tissue, is easy to assess with mammography, while denser breast tissue is more difficult to assess. On a mammogram, denser breast tissue, such as glands and connective tissue, appears white, while fat appears black. Tumors also appear white on a mammogram. Thus, dense, but normal, breast tissue surrounding a tumor can mask the tumor's presence. It has been demonstrated that higher breast density decreases mammography screening effectiveness by increasing the false-negative rate (Fajardo et al., 1988; Kolb et al., 2002). Moreover, dense mammography patterns decrease radiologists' confidence, leading to more false-positive diagnoses also. These false-positive diagnoses expose patients to unnecessary invasive procedures, such as fine needle aspirations and biopsies, causing both distress and additional health costs.
Given the negative implications of dense breast tissue, methods to reduce breast density are of particular interest. Some reduction can be achieved by carefully following specific dietary guidelines. For instance, adoption of a low-fat (mean, 21% of calories), high-carbohydrate (mean of 61% of calories) diet for 2 years has been shown to reduce the area of mammographic density (Boyd et al., 1997). Also, it has been suggested that a diet containing high amounts of soy may reduce breast density. Results from dietary approaches can be highly variable though. Moreover, ensuring patient compliance with strict dietary approaches is difficult at best.
For post-menopausal women on hormone replacement therapy (HRT), discontinuation of the therapy can decrease breast density (Rutter et al., 2001; Harvey et al., 1997). This approach to reducing breast density has obvious drawbacks. First, it can only work for women on hormone replacement therapy. A large population of women with dense breasts are not on hormone replacement therapy, particularly young women. Second, withdrawal from hormone replacement therapy effects broad systemic changes, and deprives women of HRT's therapeutic benefits. Third, and perhaps most importantly, this approach also can mask an existing tumor. Many breast tumors are hormone receptor positive, meaning that they could regress in response to cessation of hormone replacement therapy, but resume growth upon resumption of hormone replacement therapy. Harvey et al., 1996, report such an occurrence, for instance.
Another approach to reducing breast density entails chemically modulating the effect of hormones on breast tissue. One example of this involves administering a hormonal contraceptive that reduces circulating estrogen and progestogen levels (Spicer et al., 1994; Ursin et al., 1998). However, such hormonal contraceptives have broad systemic effects beyond breast tissue.
Another example involves administering the cancer drug tamoxifen, which has shown some promise for reducing breast density. Tamoxifen's effects on the breast are primarily anti-estrogenic, and mammographic patterns of density appear to be altered by oral tamoxifen. For example, studies have demonstrated a significant change toward a less dense mammographic pattern in the contralateral breasts of postmenopausal breast cancer patients treated with 20 mg/day tamoxifen (Atkinson et al., 1999; Brisson et al., 2000). More dramatic reductions occur in premenopausal patients, who tend to have more dense breasts (Son et al., 1999). Son et al. observed decreased breast parenchyma in 59.8% of women treated with 20 mg/day of tamoxifen after surgery for breast cancer. In premenopausal women, Son found an 87% decrease, compared to only 36% of patients who had not received tamoxifen, and only 10% of healthy control subjects.
Tamoxifen has significant drawbacks in this context. Its action potentially impacts on every estrogen receptor in the body, and, as both an agonist and antagonist, tamoxifen provokes a wide range of systemic effects. These effects increase the risk of endometrial cancer, endometrial hyperplasia and polyps, deep vein thrombosis and pulmonary embolism, changes in liver enzyme levels, and ocular disturbances, including cataracts. Additionally, patients treated with oral tamoxifen reported having hot flashes, vaginal discharge, depression, amenorrhea, and nausea (Fentiman 1986; Fentiman 1988; Fentiman 1989; Ibis 2002).
Thus, an effective approach to reducing breast density would offer significant benefit if it also provoked few systemic side effects.